Introduction: Frailty is characterized by vulnerability to declining health and increased risk for adverse health outcomes. Measuring frailty would be beneficial for developing interventions and assessing healthcare resource needs. No standardized measurement tool for frailty has been established. The objective of this thesis was to evaluate the frailty of participants in the Canadian Longitudinal Study on Aging (CLSA). Methods: A Frailty Index (FI) was constructed for CLSA participants based on the cumulative deficit theory of frailty. Exploratory factor analysis was conducted to study the underlying constructs of frailty and identify key factors. A hypothesized measurement model for frailty was specified. The model was modified and tested using structural equation modelling (SEM) to improve goodness-of-fit. A new frailty measurement tool was created and the construct validity of the new tool and the Frailty Index were evaluated. Results: A FI was calculated for 20,874 CLSA participants (Mean 0.14 SD 0.07). The maximum FI value was 0.68. A model containing all hypothesized variables had good fit of the data, and all variables contributed significantly. A simplified model also showed good fit and included four domains: upper-body strength, lower-body strength, dexterity, and depressive symptoms. These results persisted in an independent dataset. A Simplified Frailty (SF) score was created based on this simplified model. The FI and SF scores showed significant agreement and associations with sociodemographic variables were as predicted. Conclusions: A FI was simple to construct in the CLSA, having good fit of the data and construct validity. These results are consistent with previous research on the cumulative deficit theory of frailty. A simplified frailty model revealed key domains of frailty and resulted in a potentially useful short screening tool. The FI is recommended as a valid and reproducible approach for measuring frailty in the CLSA and similar population datasets. / Thesis / Master of Science (MSc)

With our global aging population, low muscular strength and function significantly impact an older adult’s capacity to remain independent. Older adults experience gradual declines in physical function and mobility leading to difficulty completing activities of daily living. These difficulties are conceptualized as an expression of mobility disability or through diagnoses of clinical geriatric syndromes such as frailty. Aging physiology in the musculoskeletal system clinically translates into declines in physical function due to losses in muscular strength. Preventative interventions may be appropriate as failing to intervene until critical thresholds are reached will increase healthcare expenditure. Resistance training is a highly beneficial, cost-effective, conservative strategy for community-dwelling older adults to optimize physical resiliency through increasing muscular strength and function lost due to aging, sedentary behaviour and/or physical inactivity. Resistance training needs to be dosed appropriately for function to improve, but clinicians rarely prescribe high-load resistance training with older adults, especially those at risk for mobility decline and frailty. The overarching goal of this thesis was to evaluate the role of resistance training in managing mobility disability and prefrailty. This thesis is comprised of three studies to address this goal: (1) The role of resistance training to improve or prevent mobility disability in community-dwelling older adults: a systematic review and meta-analysis. (2) The use of High- Intensity Enhanced Resistance Training (HEaRT) to optimize independence and quality of life in older adults with or at-risk of mobility disability: a pilot randomized controlled trial. (3) An Ounce of Prevention: a substudy of pre-frail older adults from the HEaRT pilot randomized controlled trial. / Thesis / Candidate in Philosophy / As people get older, the amount of muscle they have, and their strength start to decrease. When too much strength is lost, individuals can begin to have difficulties completing tasks around their home or can be at risk for developing health issues such as disability and frailty. Strength training has been one way proposed to increase strength and physical function for those at risk for mobility disability and those at risk for frailty (prefrailty). This strength training is often of low intensity despite guidelines advocating for higher-intensity exercise. This thesis evaluates the benefit of strength training, specifically using high-load, for those with mobility disability and the safety and feasibility of high-intensity resistance training for those with prefrailty and those at risk for or with established mobility disability.

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Chronic systemic inflammation increases with age and is associated with late life diseases (e.g. sarcopenia, and frailty) but the mechanisms causing systemic inflammation are largely unknown. Our laboratory has shown that the aged microbiome increases intestinal permeability which allows bacterial products into the circulation, thus causing systemic inflammation. We do not, however, know which microbes drive this phenomenon and ultimately impact healthy or unhealthy aging. To determine the degree to which frailty, sarcopenia, and systemic inflammation can be accelerated or exacerbated via the microbiome, we colonized germfree (recipient) mice with ‘young’ (≤6 months) or ‘old’ (≥ 18 months) microbiota from specific pathogen free mice. Initially, we investigated the impact of recipient age by colonizing young and old germfree mice. Differences in sarcopenia and cellular inflammation were driven by recipient age, not microbiota age, after 6 weeks of colonization, while frailty decreased in old mice colonized with young microbiota. To further investigate the impact of the microbiota in aging, we colonized middle-aged (10-14 month) germfree mice and assessed them 6 weeks and 6 months post colonization. The aged microbiota drove an increase in frailty after 6 months of colonization. To understand the differences between young and old microbial compositions we quantified short-chain fatty acids and sequenced 16S rRNA from fecal pellets of young and old mice. We used frailty, sarcopenia, and cellular inflammation data to identify relationships with short-chain fatty acids and the microbial community. We have identified specific microbes that correlate with age, frailty, sarcopenia, and cellular inflammation from Lachnospiraceae, Akkermansiaceae and Rikenellaceae families. By understanding the role of the microbiome in healthy and unhealthy aging we can develop therapeutics to combat chronic systemic inflammation and prevent and/or reverse poor health outcomes. / Thesis / Master of Science (MSc)

Falls are the most frequent cause of unintentional injuries among older adults; afflicting 30 percent of persons aged 65 and older and more than 50 percent of persons aged 85 and older. There is a serious need for strategies to prevent falls in elderly individuals, but an important challenge in fall prevention is the paucity of objective evidence regarding the mechanisms that lead directly to falls. There exists no mechanisms about how to predict and manage elderly falls, which has multifactorial risk factors associated with its occurrence in the elderly. As the U.S. population continues to age, both the number of falls as well as the cost of treatment of fall injuries will continue to grow. Decades of research in fall prevention has not led to a decrease in the fall incidence; thus new strategies need to be introduced to understand and prevent falls. Aging reduces the adaptability of various physical and environmental stressors that hinder stability and balance maintenance and may therefore result in a fall. Movement variability in an individual's task performance can be used to assess the limitations of the movement control system. Maintaining variation in movement engenders flexible and adaptable modalities for elderly individuals to prevent falls in an unpredictable and ever changing external environment. Conversely, excessive variability of movement may drive the control system closer to its stability limits during balance and walking tasks. Accordingly, inertial sensors are an emerging wearable technology that can facilitate noninvasive monitoring of fall prone individuals in clinical settings. This research examined the potential of inertial sensors for use in clinical settings, and evaluated their effectiveness in comparison to mature laboratory systems (i.e., force platform and camera system). Study findings showed a relationship between movement variability and fall risk among healthy young and older adults. Further, the outcomes of this work translates to the clinical environment to better understand the health status (leading to frailty) of cardiac patients; reflected by the underlying adaptability of the control system, but requires further improvements if to be used as robust clinical tool. This research provides the groundwork for rapid clinical assessments in which its validity and robustness should be investigated in future efforts. / Ph. D.

Yes / (1) Present deprescribing experiences of patients living with frailty, their informal carers and healthcare professionals; (2) interpret whether their experiences are reflective of person-centred/collaborative care; (3) complement our findings with existing evidence to present a model for person-centred deprescribing for patients living with frailty, based on a previous collaborative care model. Qualitative design in English primary care (general practice). Semi-structured interviews were undertaken immediately post-deprescribing and 5/6 weeks later with nine patients aged 65+ living with frailty and three informal carers of patients living with frailty. Fourteen primary care professionals with experience in deprescribing were also interviewed. In total, 38 interviews were conducted. A two-staged approach to data analysis was undertaken. Three themes were developed: attitudes, beliefs and understanding of medicines management and responsibility; attributes of a collaborative, person-centred deprescribing consultation; organisational factors to support person-centred deprescribing. Based on these findings and complementary to existing evidence, we offer a model for person-centred deprescribing for patients living with frailty. Previous models of deprescribing for patients living with frailty while, of value, do not consider the contextual factors that govern the implementation and success of models in practice. In this paper, we propose a novel person-centred model for deprescribing for people living with frailty, based on our own empirical findings, and the wider evidence base. / This research was funded by the National Institute for Health and Care Research (NIHR) Yorkshire and Humber Patient Safety Translational Research Centre (NIHR Yorkshire and Humber PSTRC).

Yes / Background: The changes that occur in the microbiome of aging individuals are unclear, especially in light of the imperfect correlation of frailty with age. Studies in older human subjects have reported subtle effects, but these results may be confounded by other variables that often change with age such as diet and place of residence. To test these associations in a more controlled model system, we examined the relationship between age, frailty, and the gut microbiome of female C57BL/6 J mice. Results: The frailty index, which is based on the evaluation of 31 clinical signs of deterioration in mice, showed a near-perfect correlation with age. We observed a statistically significant relationship between age and the taxonomic composition of the corresponding microbiome. Consistent with previous human studies, the Rikenellaceae family, which includes the Alistipes genus, was the most significantly overrepresented taxon within middle-aged and older mice. The functional profile of the mouse gut microbiome also varied with host age and frailty. Bacterial-encoded functions that were underrepresented in older mice included cobalamin (B12) and biotin (B7) biosynthesis, and bacterial SOS genes associated with DNA repair. Conversely, creatine degradation, associated with muscle wasting, was overrepresented within the gut microbiomes of the older mice, as were bacterial-encoded β-glucuronidases, which can influence drug-induced epithelial cell toxicity. Older mice also showed an overabundance of monosaccharide utilization genes relative to di-, oligo-, and polysaccharide utilization genes, which may have a substantial impact on gut homeostasis. Conclusion: We have identified taxonomic and functional patterns that correlate with age and frailty in the mouse microbiome. Differences in functions related to host nutrition and drug pharmacology vary in an age-dependent manner, suggesting that the availability and timing of essential functions may differ significantly with age and frailty. Future work with larger cohorts of mice will aim to separate the effects of age and frailty, and other factors. / This work was supported by the Canadian Institutes of Health Research (CIHR) through an Emerging Team Grant to RGB, CIHR Operating Grants to Langille et al. Microbiome 2014, 2:50 Page 10 of 12 http://www.microbiomejournal.com/content/2/1/50 SEH (MOP 126018) and RAR (MOP 93718), and a CIHR Fellowship to MGIL. Infrastructure was supported by the Canada Foundation for Innovation through a grant to RGB. RGB also acknowledges the support of the Canada Research Chairs program.

Yes / Background: Skeletal muscles undergo changes with ageing which can cause sarcopenia that can result in frailty. Quantitative MRI may detect the muscle-deficit component of frailty which could help improve the understanding of ageing muscles. Aims: To investigate whether quantitative MRI measures of T2, fat fraction (FF), diffusion tensor imaging and muscle volume can detect differences within the muscles between three age groups, and to assess how these measures compare with frailty index, gait speed and muscle power. Methods: 18 ‘young’ (18–30 years), 18 ‘middle-aged’ (31–68 years) and 18 ‘older’ (> 69 years) healthy participants were recruited. Participants had an MRI of their dominant thigh. Knee extension and flexion power and handgrip strength were measured. Frailty (English Longitudinal Study of Ageing frailty index) and gait speed were measured in the older participants. Results: Young participants had a lower muscle MRI T2, FF and mean diffusivity than middle-aged and older participants; middle-aged participants had lower values than older participants. Young participants had greater muscle flexion and extension power, muscle volume and stronger hand grip than middle-aged and older participants; middle-aged participants had greater values than the older participants. Quantitative MRI measurements correlated with frailty index, gait speed, grip strength and muscle power. Discussion: Quantitative MRI and strength measurements can detect muscle differences due to ageing. Older participants had raised T2, FF and mean diffusivity and lower muscle volume, grip strength and muscle power. Conclusions: Quantitative MRI measurements correlate with frailty and muscle function and could be used for identifying differences across age groups within muscle. / JDB is funded by a National Institute for Health Research (NIHR) (and Health Education England) Clinical Lectureship. This paper presents independent research funded/supported by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC). AC and LB are funded as part of the NIHR Collaboration for Leadership in Applied Health Research and Care, Yorkshire and Humber (NIHR CLAHRC YH).